DESCRIPTION (Abstract reproduced verbatim): Neuronal precursor cells are distributed throughout the ventricular subependyma, or subventricular zone (SVZ), of the adult vertebrate forebrain. We previously found that adult precursors are more widespread, both spatially and phylogenetically, than the limited instances of adult neurogenesis in vivo might indicate. On this basis, we postulated that neuronal recruitment into the adult brain is restricted not by the distribution of neural precursors, but rather by a failure of the mature brain environment to provide permissive support of neuronal differentiation and survival. The focus of this proposal is to define the distribution, lineage potential and humoral control of the progenitor pools, in the adult human forebrain. Our aim is to elicit neuronal production in the damaged brain, by inducing endogenous precursors to resume neurogenesis, and by providing for the differentiation and survival of their neuronal progeny. To wit,1. What is the distribution of neuronal and uncommitted neural precursors in the adult human SVZ? 2. Can the adult human subependyma be deconstructed into its constituent progenitor phenotvpes? By sorting dissociates of human SVZ after transfection with P/Talphal:hGFP, can neuronal progenitors be harvested specifically, and in high yield? Can their mitotic potential be retained after neuronal commitment? Can their transmitter phenotypes be modulated? 3. Is there a distinct phenotype of neural stem cell, as rigorously defined as a self-replicating multipotential progenitor, in the adult human VZ? Using the early neural regulatory sequences for nestin a musashi proteins, coupled to GFP as reporters of phenotype, can such uncommitted progenitors be selected from adult human brain tissue? Can these cells be directed towards neurogenesis by humoral neurotrophins? 4. Is there a distinct class of hippocampal progenitor? Are adult human hippocampal progenitors multipotential or neuronally-committed? Is their native lineage potential more restricted than that of SVZ progenitors? We intend to learn enough about the biology and selective harvest of adult human neuronal progenitors to establish an operational basis for their therapeutic use. Our goal is to utilize these cells for neuronal replacement within the damaged brain, whether by activating endogenous progenitors, or implanting exogenous cells. If this work is successful, we may soon need to consider how best to train newly generated networks of replacement neurons and glia to assume lost functions, in diseases as diverse as stroke, trauma, and the neurodegenerations.